Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohn's Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci

Alex T Adams, Nicholas A Kennedy, Richard Hansen, Nicholas T Ventham, Kate R OʼLeary, Hazel E Drummond, Colin L Noble, Emad El-Omar, Richard K Russell, David C Wilson, Elaine R Nimmo, Georgina L Hold, Jack Satsangi

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.

METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.

RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10, n = 99).

CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

Original languageEnglish
Pages (from-to)1784-1793
Number of pages10
JournalInflammatory Bowel Diseases
Volume20
Issue number10
DOIs
Publication statusPublished - Oct 2014

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Epigenomics
Crohn Disease
Methylation
Genome
Genome-Wide Association Study
Leukocytes
Discriminant Analysis
DNA Methylation
Intestinal Mucosa
Area Under Curve
Intestines
Single Nucleotide Polymorphism
Pediatrics
Gene Expression
Messenger RNA
DNA
Genes

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Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohn's Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci. / Adams, Alex T; Kennedy, Nicholas A; Hansen, Richard; Ventham, Nicholas T; OʼLeary, Kate R; Drummond, Hazel E; Noble, Colin L; El-Omar, Emad; Russell, Richard K; Wilson, David C; Nimmo, Elaine R; Hold, Georgina L; Satsangi, Jack.

In: Inflammatory Bowel Diseases, Vol. 20, No. 10, 10.2014, p. 1784-1793.

Research output: Contribution to journalArticle

Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, OʼLeary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, Nimmo, ER, Hold, GL & Satsangi, J 2014, 'Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohn's Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci', Inflammatory Bowel Diseases, vol. 20, no. 10, pp. 1784-1793. https://doi.org/10.1097/MIB.0000000000000179
Adams, Alex T ; Kennedy, Nicholas A ; Hansen, Richard ; Ventham, Nicholas T ; OʼLeary, Kate R ; Drummond, Hazel E ; Noble, Colin L ; El-Omar, Emad ; Russell, Richard K ; Wilson, David C ; Nimmo, Elaine R ; Hold, Georgina L ; Satsangi, Jack. / Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohn's Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci. In: Inflammatory Bowel Diseases. 2014 ; Vol. 20, No. 10. pp. 1784-1793.
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abstract = "BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10, n = 99).CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.",
author = "Adams, {Alex T} and Kennedy, {Nicholas A} and Richard Hansen and Ventham, {Nicholas T} and OʼLeary, {Kate R} and Drummond, {Hazel E} and Noble, {Colin L} and Emad El-Omar and Russell, {Richard K} and Wilson, {David C} and Nimmo, {Elaine R} and Hold, {Georgina L} and Jack Satsangi",
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TY - JOUR

T1 - Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohn's Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci

AU - Adams, Alex T

AU - Kennedy, Nicholas A

AU - Hansen, Richard

AU - Ventham, Nicholas T

AU - OʼLeary, Kate R

AU - Drummond, Hazel E

AU - Noble, Colin L

AU - El-Omar, Emad

AU - Russell, Richard K

AU - Wilson, David C

AU - Nimmo, Elaine R

AU - Hold, Georgina L

AU - Satsangi, Jack

PY - 2014/10

Y1 - 2014/10

N2 - BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10, n = 99).CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

AB - BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10, n = 99).CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

U2 - 10.1097/MIB.0000000000000179

DO - 10.1097/MIB.0000000000000179

M3 - Article

VL - 20

SP - 1784

EP - 1793

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 10

ER -